Pharmaceutical formulations containing voriconazole

ABSTRACT

The invention provides pharmaceutical formulation comprising voriconazole, or a pharmaceutically acceptable derivative thereof, and a sulfobutylether β-cyclodextrin.

CROSS REFERENCE TO RELATED APPLICATION

This application is the National Stage filing under 35 USC §371 based onPCT/EP98/03477, published as WO 98/58677, which was filedinternationally on Jun. 2, 1998.

This invention relates to a new pharmaceutical formulation ofvoriconazole with a sulphobutylether β-cyclodextrin.

Voriconazole is disclosed in European Patent Application 0440372 (seeExample 7). It has the following structure:

and is useful in the treatment of fungal infections. Voriconazole has alow aqueous solubility (0.2 mg/ml @ pH 3), and is not stable in water(an inactive enantiomer is formed from recombination of the retro-aldolproducts of hydrolysis). Thus, development of an aqueous intravenousformulation with a sufficient shelf life is difficult. These problemsare magnified by the semi-polar nature of the compound (log D=1.8) whichmeans that it is not generally solubilised by conventional means such asoils, surfactants or water miscible co-solvents.

European Patent Application 0440372 mentions that the compoundsdisclosed therein may be formulated with cyclodextrin: however, it isnow suspected that underivatised or unmetabolised cyclodextrin has toxiceffects on the body and so is unsuitable as a pharmaceutical excipient,particularly when administered parenterally.

International Patent Application WO 91/11172 discloses sulphoalkylethercyclodextrin derivatives of formula A,

wherein

n is 4, 5 or 6;

R₁₋₉ independently represent O⁻or O—(C₂₋₆ alkylene)—SO⁻, provided thatat least one of R₁ and R₂ is O—(C₂₋₆ alkylene)—SO⁻; and

S₁₋₉ independently represent a pharmaceutically acceptable cation (suchas H⁻or Na⁻).

It has now been found that the solubility of voriconazole in water canbe increased by molecular encapsulation with sulphoalkylethercyclodextrin derivatives of the type disclosed in International PatentApplication WO 91/11172, particularly when n is 5 (a β-cyclodextrinderivative) and the cyclodextrin ring is substituted by sulphobutylgroups.

Thus, according to the present invention, there is provided apharmaceutical formulation comprising voriconazole, or apharmaceutically acceptable derivative thereof and a cyclodextrinderivative of formula I,

wherein

R^(1a-g), R^(2a-g) and R^(3a-g) independently represent OH orO(CH₂)₄SO₃H; provided that at least one of R^(1a-g) representsO(CH₂)₄SO₃H; or a pharmaceutically acceptable salt thereof.

Pharmaceutically acceptable salts of particular interest are salts ofthe O(CH₂)₄SO₃H groups, for example alkali metal salts, such as sodiumsalts.

Preferably, the average number of O(CH₂)₄SO₃H groups per molecule offormula I is in the range 6.1-6.9, for example 6.5. This enhancesmolecular encapsulation resulting in enhanced voriconazole solubility.This effect would not be anticipated because increasing the degree ofsubstitution increases steric hindrance around the cavity of thecyclodextrin and would be expected to reduce complexation efficiency.

It is preferred that each O(CH₂)₄SO₃H present is in the form of analkali metal salt (such as the sodium salt). This enhances the affinityof the molecule for voriconazole, which is unexpected becausevoriconazole is not charged.

Preferably, the formulation is for parenteral administration, forexample, i.v. administration.

The aqueous stability of the voriconazole-cyclodextrin derivativecomplex is further enhanced by lyophilisation (freeze-drying). Thecyclodextrin derivatives used in formulations according to the inventionenable the finished lyophilised product to accommodate high levels ofmoisture (up to 3.0%) without a detrimental effect on stability.Furthermore, the use of such cyclodextrin derivatives controls andminimises the formation of the inactive enantiomer of voriconazole.

Generally, in aqueous intravenous and intramuscular formulationsaccording to the invention, the voriconazole will be present at aconcentration of from 5 mg/ml to 50 mg/ml, for example 10 mg/ml to 30mg/ml. The cyclodextrin derivative of formula I will be present in amolar ratio of voriconazole:cyclodextrin derivative of from 1:1 to 1:10,for example 1:2 to 1:7, in particular 1:2 to 1:3. The formulations maybe lyophilised (freeze dried) for storage prior to use, and made up withwater when required.

In the following example, the sulphobutylether β-cyclodextrin has anaverage sulphobutylether substitution of 6.5 per cyclodextrin molecule,and each sulphobutylether unit is present as its sodium salt.

EXAMPLE 1 i.v. Formulation of Voriconazole

Ingredient Specification mg/ml Voriconazole Pfizer 10.000Sulphobutylether β-cyclodextrin Pfizer 160.000 Water for injections Ph.Eur. to 1.000 ml Total 1.000 ml

Method:

1. With constant stirring, add the sulphobutylether β-cyclodextrin(SBECD) to 80% of the final volume of water for injections, and continueto stir until all the SBECD has dissolved.

2. Add the voriconazole and dissolve with stirring.

3. Make the solution up to volume with water for injections.

4. Filter the resulting solution through a sterile 0.2 mm nylon filterinto a sterile container.

5. Fill 20 ml volumes into sterile freeze drying vials and stopper.Lyophilise.

What is claimed is:
 1. A pharmaceutical formulation comprisingvoriconazole and a cyclodextrin derivative of formula I,

wherein R^(1a-g), R^(2a-g) and R^(3a-g) independently represent OH orO(CH₂)₄SO₃H; provided that at least one of R^(1a-g) representsO(CH₂)₄SO₃H; or a pharmaceutically acceptable salt thereof; and whereinsaid formulation has been lyophilized.
 2. A formulation as claimed inclaim 1, wherein the average number of O(CH₂)₄SO₃H groups per moleculeof formula I is in the range 6.1-6.9.
 3. A formulation as claimed inclaim 1 wherein each O(CH₂)₄SO₃H present is in the form of an alkalimetal salt.
 4. A formulation as claimed in claim 1, which is adapted forparenteral administration.
 5. A formulation as claimed in claim 1,wherein the cyclodextrin derivative of formula I is present in a molarratio of voriconazole:cyclodextrin derivative of from 1:1 to 1:10.
 6. Asolution made by making up a lyophilized formulation, as claimed inclaim 1, in water.